The study aims at identifying protective immune responses that reduce malaria disease and parasite burden in young children. This study is based on our earlier studies of pregnancy malaria. Susceptibility to pregnancy malaria (PM) results from the unique binding phenotype of placental parasites that adhere to chondroitin sulfate A (CSA). Over successive pregnancies, women develop specific humoral immunity to placental parasites in the form of anti-adhesion antibodies. Anti-adhesion antibodies are associated with improved pregnancy outcomes. To better understand malaria pathogenesis in pregnant women, and the development of immunity in young children, we established a longitudinal birth cohort in Mali in which women were enrolled during their pregnancy and their newborn children actively followed up from birth up to 5 years. Blood samples collected from pregnant women and children at fixed time points and at the time of infection are used to: 1. Assay soluble mediators; 2. Describe parasite binding phenotype; 3. Characterize parasite membrane proteome; 4. Measure anti-adhesion antibodies; 5. Assess disease biomarkers The pathological hallmark of P. falciparum parasites is their sequestration in deep vascular beds of various tissues. Because parasite adhesion has been associated with disease, antibodies that block this activity may confer protective immunity. We examined the association between levels of plasma anti-adhesion activity and surface reactivity against freshly collected IEs from malaria-infected children in plasma samples collected from children participated in a Malian birth cohort. We described that antibody levels that inhibit the binding of childrens IE to the receptors ICAM-1, integrin 31 and laminin increased with age. The breadth of antibodies that inhibit ICAM-1 and laminin adhesion (defined as the proportion of IE isolates whose binding was reduced by >=50%) also significantly increased with age. The number of malaria infections prior to plasma collection was associated with levels of plasma reactivity to IE surface proteins, but not levels of anti-adhesion activity. In FY19 we expanded our immunopathogenesis studies of pregnancy malaria to characterize macrophage subpopulation in the placenta using immunofluorescence studies of tissue and other approaches. For the study of disease biomarkers, we conducted a pilot study in FY19 of comparative metabolomics of samples collected from children with and without severe malarial anemia. The metabolomic data will be integrated with the proteomics data collected from the same samples and further validate changes associated severe malaria.